The effective toxicological evaluation of skin sensitization demands that potential contact allergens are identified and that the likely risks of sensitization among exposed populations assessed. By definition, chemicals which possess the toxicological property of skin sensitization potentially are capable of causing allergic contact dermatitis (ACD) in humans. However, this hazard is not an all-or-none phenomenon; clear dose-response relationships can be discerned and thresholds identified for both the induction of sensitization and the elicitation of contact dermatitis. Commonly, these parameters are grouped under the heading of potency, determination of which is vital for risk assessment. In the present investigation, the local lymph node assay (LLNA) has been employed to determine the relative potency of a range of 20 chemicals. The parameter used is the estimated concentration required to produce a 3-fold increase in draining lymph-node cell proliferative activity, the EC3 value. These measurements have been compared with an assessment of the human sensitizing potency of the 20 selected chemicals, each being assigned to 1 of 5 classes based on their human sensitizing potency. The EC3 value, derived from LLNA work carried out in acetone/ olive oil vehicle, correlated well with the human classification, with the strongest sensitizers having low EC3 values (
Skin-sensitizing chemicals exhibit dose-response relationships for the elicitation of contact dermatitis. Previously, considerable work has been carried out in which the elicitation of allergic skin reaction has been examined as a function of the applied concentration. However, the relationship between exposure time, dose and response has not been explored in any depth. The present work has extended our initial assessment of the relationship between both exposure time and concentration for para-phenylenediamine (PPD) in a group of 19 PPD-allergic volunteers. The results clearly demonstrate that a relationship exists between both exposure time and concentration. Positive responses to PPD were directly proportional to exposure time: at 5 min 16% responded; at 15 min, 38%; at 30 min, 50%; and at 120 min, 69%. A similar direct relationship was found between concentration of PPD and response: after 120 min, 22% of patients had responded to 0.01%, and 69% to 1% PPD. All exposures for 1 and 2 min were negative. Subsequent evaluation using repeated 5 min open application testing demonstrated a cumulative effect, as after 8 days 39% of the panel reacted, more than double the number that reacted to a single occluded 5-min treatment. It was noted that there was marked subject variability in exposure time and dose required to elicit an allergic response. These results are of relevance for the general interpretation of patch test data, especially with regard to risk assessment.
The murine local lymph node assay (LLNA) is a predictive test for the identification of chemicals that have the potential to cause skin sensitization. Since its original development, the assay has been the subject of national and international evaluation studies and extensive comparisons with guinea pig tests and human data. On the basis of these investigations, the LLNA has recently been endorsed by ICCVAM (Interagency Coordinating Committee on the Validation of Alternative Methods) as a stand-alone method for skin sensitization hazard identification. At the same time, ICCVAM confirmed that, although the LLNA is not an in vitro method, it does represent a refinement in the way animals are used and can provide a means for reducing the number of animals used in sensitization hazard assessment. The investigations described here were designed to explore further the ability of the LLNA to identify accurately those chemicals that cause allergic contact dermatitis in humans. To that end we have measured, amongst 3 independent laboratories, LLNA responses induced by a total of 18 test chemicals, 11 of which are known to cause skin sensitization and 7 of which are believed not to be associated with any significant evidence of allergic contact dermatitis in humans. The LLNA correctly classified 16 of the 18 materials. The 11 chemicals tested which are associated with allergic contact dermatitis in humans were found to be positive in the LLNA. Of the 7 materials believed to be non-sensitizers, 5 were negative in the LLNA and 2 produced positive results. Collectively, these data provide additional evidence that the LLNA is able to discriminate skin sensitizers from those chemicals which do not possess a significant skin sensitization potential and thus provides a method for hazard identification that offers important animal welfare benefits.
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